Compound (R) -N*6*-ethyl-6, 7-dihydro-5H-indeno (5, 6- d) thiazole-2, 6-diamine and the use as antipsychotics

A compound, 6-d technology, applied in nervous system diseases, medical preparations containing active ingredients, organic chemistry, etc., can solve problems such as limitations and lower patient compliance

Inactive Publication Date: 2011-01-19
ASTRAZENECA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, extrapyramidal side effects ("EPS") and / or elevated prolactin levels limit the number of patients who can receive certain current medications and reduce patient compliance

Method used

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  • Compound (R) -N*6*-ethyl-6, 7-dihydro-5H-indeno (5, 6- d) thiazole-2, 6-diamine and the use as antipsychotics
  • Compound (R) -N*6*-ethyl-6, 7-dihydro-5H-indeno (5, 6- d) thiazole-2, 6-diamine and the use as antipsychotics
  • Compound (R) -N*6*-ethyl-6, 7-dihydro-5H-indeno (5, 6- d) thiazole-2, 6-diamine and the use as antipsychotics

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] Example 1. (R)-N 6 -Synthesis of ethyl-6,7-dihydro-5H-indeno[5,6-d]thiazole-2,6-diamine

[0081] Scheme A below illustrates the synthesis of (R)-N 6 - The method of ethyl-6,7-dihydro-5H-indeno[5,6-d]thiazole-2,6-diamine.

[0082] Option A

[0083]

[0084] The synthesis is carried out as follows:

[0085] Step A. Synthesis of ((S)-5-bromo-indan-2-yl)-benzyl carbamate

[0086]

[0087] To (S)-5-bromo-indan-2-ylamine (1R)-(-)-10-camsylate (109.6 g, 246.8 mmol) cooled in an ice bath, as obtained by the Adv. Synth.Catal.2001, 343, prepared by the method given in pp 461-472) in CH 2 Cl 2 To the suspension in (1 L) was added DIEA (10 mL, 617 mmol) followed by benzyl chloroformate (36.5 mL, 259 mmol) dropwise over 5-10 minutes. The mixture was stirred for 2 h, during which time H was added 2 O (100 mL). The phases were separated and the organic phase was washed with 1M HCl (about 100 mL), H 2 O (about 100 mL) and saturated NaHCO 3 Aqueous solution (about 100mL...

Embodiment 2

[0116] Example 2. (R)-N 6 -Scale-up synthesis of ethyl-6,7-dihydro-5H-indeno[5,6-d]thiazole-2,6-diamine

[0117] Reaction Scheme A is scaled up approximately tenfold. Scale-up reactions were performed in a manner similar to that performed in Reaction Scheme A, except for the scale and the following differences:

[0118] In a scaled-up version of the method in Step A, the solvent consists of CH 2 Cl 2 into acetonitrile. This allowed product isolation by addition of water and subsequent filtration of the product. This scale-up method benefits from the absence of an extractive workup and the absence of halogenated solvents.

[0119] In the scale-up process, it was determined that the distillation of benzophenoneimine in step C was not necessary. Therefore, the distillation process was omitted without compromising the imine formation.

[0120] In steps E and F of the scaled-up method, the crude hydrolyzate was dissolved in toluene instead of CH 2 Cl 2 dissolved in. The b...

Embodiment 3

[0123] Example 3. In vitro assay process

[0124] The affinity (Ki) for the D2 receptor was used in [ 3 H]-raclopride (raclopride) binding assay to measure. D2 antagonism (IC 50 ) was measured with a GTPγS assay. However, the GTPγS assay cannot detect the agonistic effect of aripiprazole in the present inventors or others (Jordon S, et.al., "Dopamine D2 receptor partial agonists display differential or contrasting characteristics in membrane and cell-based assays of dopamine D2 receptor signaling," Prog Neuropsychopharmacol Biol Psychiatry, 31(2): 348-56 (March 30, 2007); Epub October 27, 2006). This highlights the limitations of using the GTPγS assay to identify D2 partial agonists. Assays that measure more downstream levels of cellular signaling such as cAMP and extracellular impedance across cell layers tend to detect agonism more sensitively to provide reliable agonism of D2 partial agonists. Changes in extracellular impedance across cell layers can be measured by cel...

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PUM

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Abstract

This invention relates to the compound of Formula I and pharmaceutically acceptable salts thereof: (I) (R)-N*6*-ethyl-6,7-dihydro-5H-indeno[5,6-d]thiazole-2,6-diamine. This invention also relates to methods of making, methods of using, and pharmaceutical compositions comprising the compound of Formula I and salts thereof.

Description

[0001] This patent claims priority to US Provisional Application 61 / 030,332 (filed February 21, 2008). The entire content of this patent application is incorporated into this patent by reference. technical field [0002] The present invention relates to novel compounds and their use as antipsychotics. Specifically, the present invention relates to compounds (and salts thereof) having partial dopamine D2 receptor agonistic activity, methods for preparing the compounds and salts thereof, and uses of the compounds and salts thereof for therapeutic and drug screening purposes. Background technique [0003] Clinicians routinely use antipsychotics that block dopamine D2 receptors. Antipsychotics are generally divided into "typical" and "atypical" antipsychotics. Atypical antipsychotics generally have a lower incidence of side effects than typical antipsychotics. Only a few dopamine-depleting agents (other than those that provide D2 receptor blockade) achieve antipsychotic activ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/82A61K31/428A61P25/16A61P25/18A61P25/24A61P25/30
CPCC07D277/82A61P25/00A61P25/14A61P25/16A61P25/18A61P25/24A61P25/30A61P25/36A61P43/00A61P5/06
Inventor 威廉·C·布莱克韦尔三世詹姆斯·赫尔西泽刘建伟加里·斯蒂尔曼丽贝卡·厄巴尼克丹·威德佐夫斯基吴叶
Owner ASTRAZENECA AB
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